Calcium is an essential mineral nutrient, needed for formation of strong bones and healthy teeth, and is involved in helping blood to clot. It is also required to transmit nerve signals, and for muscle contraction, heartbeat, glandular secretion and maintenance of immune function. Calcium is found in nutritionally useful amounts in a variety of foods including milk and other dairy products, as well as in green vegetables such as spinach, in nuts and in fish with bones such as sardines. Usually, nutritional requirements for calcium are met from the diet. However, when there is insufficient calcium in the diet to meet the body's needs, supplements are needed to prevent calcium deficiency. Calcium supplements can be of value even where overall dietary intake of calcium is adequate, for example to even out day-to-day or week-to-week variations in intake and provide a “margin of error” in satisfying daily nutritional requirement.
In addition to helping meet dietary requirements, calcium supplementation has pharmaceutical application, for example in preventing or treating osteoporosis that is characterized by loss of normal bone density and by bone fragility. Among various factors, a chronic shortage of dietary calcium is a key factor contributing to osteoporosis development. Thus administration of a calcium supplement can be therapeutically beneficial, for example to prevent or ameliorate osteoporosis-related symptoms.
Calcium supplements may also provide benefits in reducing colonic mucosal proliferation, which in turn can lower risk of colorectal cancer; lowering systolic blood pressure in hypertensive patients; lowering serum cholesterol in some individuals, with attendant benefits such as lowering risk of stroke; ameliorating symptoms of premenstrual syndrome; and in reducing weight gain in subjects who are obese or at risk of obesity. See, for example, PDR for Nutritional Supplements, Thomson P D R, Montvale, N.J., pp. 74-79 (2001).
Absorption of calcium in the small intestine depends on the action of 1,25-dihydroxycholecalciferol, a metabolite of vitamin D. For this reason, some calcium supplements include a source of vitamin D such as vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol).
Numerous calcium (Ca2+) salts are available for oral use as calcium supplements. Among salts that can effectively be used for calcium supplementation, calcium carbonate and calcium phosphate have the highest elemental calcium content (about 40%). Other salts include calcium citrate (about 21% calcium), calcium lactate (about 13% calcium) and calcium gluconate (about 9% calcium). A common adult daily dose for calcium supplementation is 1200 mg, which is typically provided as two tablets each comprising 600 mg calcium, for example in the form of calcium carbonate. A 600 mg calcium dose is provided by about 1500 mg calcium carbonate. The need for such a large amount of calcium carbonate results in a tablet having a large volume that some consumers or patients find difficulty or feel discomfort in ingestion. This in turn can lead to reduced patient compliance. Even a 300 mg calcium tablet (containing about 750 mg calcium carbonate) is uncomfortably large for some people. It is noteworthy that elderly people, one of the subpopulations that are most prone to osteoporosis, often have especial difficulty in swallowing large dosage forms. Therefore, there is a need for a smaller volume calcium composition that is easier to swallow.
Calcium carbonate tablets are generally prepared by first granulating calcium carbonate powder, typically with a binder, and then compressing the resulting granulation. Calcium carbonate powders are available in two main forms, precipitated and ground. Precipitated calcium carbonate, prepared from limestone by recarbonation and precipitation of calcium carbonate from a solution, is often used and is typically preferred in tablet making for its small particle size and good compressibility. However, precipitated calcium carbonate has a high surface area and differs in its surface chemistry from other forms of calcium carbonate. These properties tend to lead to low density granulations that, on compression, produce relatively large volume dosage forms.
Efforts to develop a lower volume calcium supplement dosage form have included use of alternative Ca2+ salts such as calcium citrate. For example, U.S. Pat. No. 6,818,228 to Walsdorf et al. mentions a dietary supplement comprising a high bulk density form of calcium citrate.
Ground calcium carbonate tends to have higher bulk density than precipitated calcium carbonate and is sometimes described in the art as “heavy calcium carbonate.” However, it poses its own challenges when used to prepare tablets. Haines-Nutt, J. Pharm. Pharmac. 28:468-470 (1976) reported that compacts made up from heavy calcium carbonate are weaker and more friable than similar compacts prepared from heavy magnesium carbonate, and speculated that this might result from absence of water of crystallization in calcium carbonate.
U.S. Patent Application Publication No. 2005/0025811 of Levin et al. relates to highly compactable calcium carbonate granulations and methods for preparing such granulations. The granulations are reportedly prepared by mixing calcium carbonate powder and excipients such as maltodextrin and mineral oil in a mixer capable of creating high shear, and then drying the resulting composition, for example in a fluidized bed convection oven. The calcium carbonate powders used include products known to be ground calcium carbonate (e.g., OMYA-Cal™ FG). Particle size of the calcium carbonate is said to have an effect on compactability of the granulation formed; in the broad median particle diameter range of about 0.1 to about 20 μm, a median particle diameter between about 10 and about 12 μm is said to be preferred. Combinations of larger and smaller particle size powders are also said to be useful. Tablets prepared from such granulations are said to have densities about 20% to at least about 35% greater, and to be about 20% to at least about 35% smaller in volume, than commercially available calcium supplement tablets. Specific examples of tablets containing “600 mg calcium carbonate” (600 mg calcium in the form of calcium carbonate may be intended) are reportedly about 20% smaller in volume than CALTRATE® brand 600 mg tablets.
Product labeling for CALTRATE® 600 of Wyeth makes clear that each tablet contains 600 mg calcium, as calcium carbonate (i.e., about 1500 mg calcium carbonate). The tablet also contains an unspecified amount of starch and <2% croscarmellose sodium, magnesium stearate and titanium dioxide. It is further stated that the tablet may contain <2% of glycerin, methylcellulose, polydextrose, polyethylene glycol, polyvinyl alcohol and talc. See http://www.caltrate.com/products/caltrate600_lbl.asp.
Other commercially available calcium supplement tablets can vary from the above in composition. For example, the product label for FINEST NATURAL™ Calcium 500+D caplets sold by Walgreens states that each caplet contains 500 mg calcium as calcium carbonate (i.e., about 1250 mg calcium carbonate), and 125 IU (i.e., about 3 μg) vitamin D as cholecalciferol. Other ingredients listed are croscarmellose sodium, sodium lauryl sulfate, hydroxypropylmethylcellulose (HPMC), titanium dioxide, magnesium stearate, polyethylene glycol and carnauba wax.
There remains a need in the art for alternative calcium carbonate dosage forms having low volume to improve ease of swallowing, yet having acceptably low friability coupled with rapid disintegration and dissolution upon ingestion, and methods to prepare such dosage forms.